Worldwide, approximately 2% of the population is infected with Hepatitis C virus (HCV) and 50-80% of those develops into persistent infections and are at great risk of developing hepatocellular carcinoma. Currently, the only approved therapy for treatment of chronic HCV infection is a combination of type I interferon (IFNa/p) and ribavirin with a response to treatment between 42% and 82% sustained viral clearance. Even in patients without sustained responses, IFN therapy usually results in a rapid decline in HCV viral load; therefore, IFN will likely continue to be used in treatment either in combination therapies or as an initial pre-treatment to reduce viral load, despite the development of other antivirals. The mechanisms of actions of IFN (or resistance to IFN) during antiviral therapy for HCV are not clear; yet, understanding these mechanisms is critical for interpretation of future antiviral treatments for HCV. MicroRNAs (miRs) represent a newly identified non-coding RNA species that promotes mRNA degradation and/or attenuates protein translation, thus providing additional post-transcriptional control over protein expression levels. We recently discovered that interferons transcriptionally regulate numerous cellular microRNAs (miRs). Six of these IFNo/p-induced miRs have predicted targets within the HCV genomic RNA. Even more intriguing, we also found that IFNo/p potently inhibit the expression of a liver- specific miR that has been demonstrated to be absolutely indispensible for replication of HCV. Our preliminary findings lead us to the hypothesis that IFN-mediated inhibition of HCV replication involves the induction or suppression of cellular miRs. The studies outlined in this proposal are aimed to elucidate the molecular mechanism underlying the IFNa/p-mediated suppression of HCV replication through modulation of the expression of cellular miRs. In addition, we propose to analyze the expression levels of these interferon-regulated miRs during the course of clearing or persistent HCV infections. Our model offers not only a new molecular basis by which IFNa/p specifically attenuate HCV infection, but also provides a novel mechanistic paradigm for the antiviral actions of interferons. [unreadable] [unreadable] [unreadable]